3-guanidinoalkyl-thiophene-compositions

ABSTRACT

3-Guanidinoalkyl-thiophenes, e.g. those of the formula   R1,2 H, alkyl or halogen R3,4 H or alkyl N 1-4 R5,6 H, alkyl or alkylene AND SALTS THEREOF ARE ANTIHYPERTENSIVES.

United States Patent [191 Werner et al.

[ 1 June 18, 1974 S-GUANIDINOALKYL-THIOPHENE- COMPOSITIONS [75] Inventors: Lincoln Harvey Werner, Summit;

Neville Finch, West Orange, both of NJ.

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: Sept. 18, 1972 [21] Appl. No.: 290,036

[52] US. Cl 424/275, 424/229, 424/251,

424/273 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/251, 250, 273, 275

[56] References Cited UNITED STATES PATENTS 3,242,194 3/1966 Walton et al 260/329 AM 3,247,221 4/1966 Augstein et a1 260/3096 3,330,838 7/1967 Augstein et a1 .1 260/3096 3,401,201 9/1968 Walton 260/329 AM Primary ExaminerAlbert T. Meyers Assistant ExaminerNorman A. Drezin Attorney, Agent, or Firm-Joseph G. Kolodny; Theodore O. Groeger 7] ABSTRACT 3-Guanidinoalkyl-thiophenes, e.g. those of the formula R, =l-l, alkyl or halogen R =H or alkyl n=l4 R =l-l, alkyl or alkylene and salts thereof are antihypertensives.

4 Claims, N0 Drawings 3-GUANIDINOALKYL-THIOPHENE- COMPOSITIONS- CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of application Ser. No. 109,957, filed Jan. 26, 1971, (now US. Pat. No. 3,746- ,724) which in turn is a continuation-in-part of application Ser. No. 28,029, filed Apr. 13, 1970 (now abancloned).

BACKGROUND OF THE INVENTION According to Walton et al (U.S. Pat. No. 3,242,l94), antihypertensive 2'thenylguanidines can be prepared by the reaction of a thenylamine or a salt thereof with an S-substituted isothiourea or a salt thereof. Said 2- thenylguanidines are, in contrast to guanethidine, rather short-acting depressants of the sympathetic nerve function" and dosing two or three times a day is usually desirable. Said teaching of Walton et al. can,- not be applied to the preparation of corresponding 3- thenylguanidines, because 3-thenylamines are not available according to the methods used in the preparation of 2-thenylamines.

According to the present invention, new 3-guanidino-alkyl-thiophenes (including 3- thenylguanidines) are provided, which surprisingly exhibit outstanding hypotensive effects in the anesthetized normotensive dog, as well as in the unanesthetized renal hypertensive dog. More surprisingly, said effects are of the desired order of duration. Thus, the 3-thenylguanidines of the present'invention are shorter acting then guanethidine, but longer acting than the 2- thenylguanidines of Walton et al.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 3-guanidinoalkyl-thiophenes or salts thereof, more particularly of those corresponding to Formula I wherein each of R, and R is hydrogen, lower alkyl or halogeno, each of R and R is hydrogen or lower alkyl, R and R separately are hydrogen or lower alkyl or, when taken together, lower alkylene separating the adjacent nitrogen atoms by at least 2 carbon atoms and n is an integer from 1 to 4, or of therapeutically useful acid addition salts thereof, as well as of corresponding pharmaceutical compositions and of methods for the preparation and application of these products. Said products are useful antihypertensive agents in the treatment or management of the various forms of hypertension.

DESCRIPTION OF THE PREFERRED EMBODIMENT The lower alkyl radicals R, to R primarily represent methyl, but also, for example, ethyl, nor i-propyl or -butyl. A lower alkylene radical R +R is preferably 1,2-ethylene or l,3-propylene, but also, for example, 1,2-propylene, l,2-, l,3-, 1,4- or 2,3-butylene. A halogen atom R or R is primarily chloro or bromo, but also, for example, fluoro. The alkylene radical C,,H represents preferably methylene or ethylidene, but also, for example, one of the alkylene radicals mentioned for R +R The term lower", referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to 7, preferably up to 4 carbon atoms.

Salts of the 3-guanidinoalkyl-thiophenes are preferably therapeutically useful acid addition salts, for example, those derived from inorganic acids, such as strong metalloidic acids, for example, hydrohalic, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, such as carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyrorac'emic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; methionine, tryptophan, lysine or arginine.

The compounds of the invention exhibit valuable pharmacological properties, especially hypotensive and antihypertensive effects. This can be demonstrated in animal tests, using advantageously mammals, such as dogs, as test objects. The compounds of the invention can be applied enterally or parenterally, for example, orally (or directly into the lumen of the small intestine) or intraveneously, for example, within gelatin capsules or in the form of aqueous solutions or suspensions respectively. The applied dosage may range between about 0.5 and 50 mg/kg/day, preferably between about 1 and 10 mg/kg/day, advantageously at about 3 mg/kg/day. The lowering effect on the blood pressure is observed either in the anesthetized normotensive dog after i.v. drug administration or in the unanesthetized, renal hypertensive dog after oral drug administration, as described, for example, by A. .l. Plummer in Medicinal Chemistry VI (1967), Antihypertensive Agents, page 67 (Academic Press Inc., N.Y.). Accordingly, the compounds of the invention are useful antihypertensive agents, for example in the treatment or management of primary or secondary hypertension, e.g. essential or renal hypertension. They are also useful intermediates in the preparation of other valuable products, especially of pharmacologically active agents.

Particularly useful are the compounds of Formula I, in which each of R and R is hydrogen, alkyl or halogen, each of R and R is hydrogen, R and R separately are hydrogen or alkyl or, when taken together alkylene separating the adjacent nitrogen atoms by at least 2 carbon atoms, said alkyl or alkylene groups contain up to 4 carbon atoms and n is an integer from 1 to 3, or therapeutically useful acid addition salts thereof.

Especially valuable are compounds of Formula II wherein each of R and R is hydrogen, methyl, chloro or bromo, each of R R and R is hydrogen or methyl or R and R together represent 1,2-ethylene, more 3 particularly the l-(3-ethenyl)-2,3-dimethylguanidine, or therapeutically useful acid addition salts thereof, which exhibit in the renal hypertensive dog a high order of antihypertensive effects, lasting about one day.

The compounds of the invention are prepared according to methods known for the preparation of substituted guanidines. For example, the process for their preparation consists in:

a. reacting a corresponding 3-aminoalkyl-thiphene with a corresponding cyanamide, lguanylpyrazole, guanidine or, advantageously, an etherified pseudourea or thiopseudourea or b. ammonoor aminolyzing a corresponding thienyl- (3 )-alkylcyanamide, -urea or -thiourea or, advantageously, an O- or S-ether of the corresponding pseudoureas or c. reducing a thienyl-(3)-alkanoylguanidine and, if desired, converting a resulting compound into another compound of the invention.

Ethers of the pseudoureas mentioned under items (a) and (b) are, for example, the lower alkyl ethers, such as the methyl, ethyl, propyl or butyl ethers. The other reactants mentioned are unsubstituted or correspondingly substituted by R R provided that both the 3-aminoalkyl-thiophene mentioned under (a) and the aminolyzing agent mentioned under (b) contain at least one hydrogen atom bound to nitrogen. The lguanylpyrazoles may also contain substituents, besides those in the guanyl group, for example, lower alkyl in the 3- and/or 5-position.

The reduction according to item (c) can be performed with the use of simple or complex light metal hydrides, such as boro-hydrides or, preferably, alkali metal or alkaline earth metal aluminum hydrides, e.g. lithium, sodium or magnesium aluminum-hydride, If necessary, activators, such as aluminum chloride, may be used in said reduction. I

The compounds of the invention so obtained can be converted into each other according to methods known per se. For example, unsubstituted guanidines can be substituted in the guanidino group by aminolyzing them with monoor di-lower alkylamines analogous to reaction (b). Furthermore, the compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the above process is carried out. A resulting free base can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, preferably a therapeutically useful acid, or with a corresponding anion exchange preparation, and isolating the desired salt. An acid addition salt may be converted into the free compound by treatment with a base, e.g. a metal hydroxide, ammonia or a hydroxy] ion exchange preparation.

These or other salts, for example, the picrates, can also be used for purification of the resulting free compounds, which are converted into salts, the salts separated and the free compounds liberated from the salts. in view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can likewise be resolved into the optional antipodes, for example, by separation of disastereomeric salts thereof, e.g. by the fractional crystallization of dor l-tartrates.

The above reactions are carried out according to standard methods, in the presence or absence of dilu' ents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing, neutralizing agents and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure For example, any generated mineral or sulfonic acid may be neutralized with inorganic or organic bases, such as alkali or alkaline earth metal hydroxides, carbonates or bic arbonates or nitrogen bases, such as tri-lower alkylamines or pyridine.

The invention also comprises any modification of the above process, wherein a compound resulting as an intermediate at any stage thereof, is used as starting material and the remaining steps are carried out or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions or is used in the form of its salts or reactive derivatives. For example, in the reaction according to item (a) the cyanamide may be formed in situ from a nitroso-guanidine, e.g. methylcyanamide from l-nitroso3-methylguanidine. The ammonia, primary or secondary amine used according to item (b) may also be released during the reaction from corresponding salts or addition compounds, such as ammonium sulfate, methylammonium acetate or hexamethylenetetramine. Preferably one of the reactants mentioned under (a) and (b) is used in the form of its salt, which especially is derived from an inorganic acid, such as a hydrohalic, phosphoric, nitric or advantageously sulfu ric acid. Also metal salts may be used, especially those from cyanamides, which advantageously are alkali or alkaline earth metal salts.

The starting material mentioned under items (b) and (c) is new and is considered as additional subject matter of the present invention. it can be prepared from corresponding 3-alkylthiophenes by halogenation with an N-halogeno-succinimide, advantageously brominated with N-bromo-succinimide. The resulting 3-(a-halogenoalkyl)-thiophene is then reacted either with ammonia, R -,NH or, advantageously, an alkali metal (e.g. potassium) phthalimide, and the resulting N-substituted phthalimide subjected to hydrolysis or hydrazinolysis. Said 3-(a-halogenoalkyl)-thiophenes can also be obtained from 3-alkanoyl-thiophenes by re duction with simple or complex light metal hydrides and the resulting alcohols esterified with reactive derivatives of the corresponding acids, such as thionyl or phosphorus halides or oxyhalides. The resulting 3-(01- halogenoalkyl)-thiophenes can also be reacted with alkali metal cyanides and the resulting nitriles reduced, for example, with catalytically activated hydrogen, e.g. hydrogen in the presence of Raney nickel, or with said complex light metal hydrides, e.g. lithium aluminum hydride, in order to obtain 3-(B-aminoalkyl)- thiophenes. The former 3-(a-aminoalkyl)-thiophenes can also be obtained by reduction of the oximes derived from said 3-alkanoyl-thiophenes, e.g. by catalytic hydrogenation. The resulting 3-(aor B-aminoalkyhthiophenes may be converted into their diazonium salts according to conventional methods, e.g. by reacting them with sodium nitrite under acidic conditions, and the resulting diazonium salts hydrolyzed by raising the temperature of the aqueous solutions thereof until nitrogen evolves, to yield the corresponding 3-(01- or B-hydroxyalkyl)-thiophenes. These may be reacted with thionyl or phosphorus halides as described above, the resulting halides reacted with alkali metal cyanides and the nitriles obtained reduced as shown above, in order to yield 3-(yor 8-aminoalkyl)-thiophenes. Resulting primary amines may be converted into the corresponding secondary amines by reacting them with reactive esters of R OH, for example, such of a strong mineral or sulfonic acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid, sulfuric acid or a lower alkane or benzene sulfonic acid, e.g. methane, ethane or p-toluene sulfonic acid. The resulting 3-aminoalkyl-thiophenes can then be converted into the starting material mentioned under item (b), for example, by reacting them with cyanogen halides, isocyanates or isothiocyanates and, if desired, etherifying resulting ureas or thioureas with reactive esters of alkanols, e.g. those mentioned above, in order to obtain the O- or S'alkyl-pseudoureas.

The starting material mentioned under item (0) can be prepared by hydrolyzing the above-mentioned nitriles with strong acids or alkalies, e.g. sulfuric acid or potassium hydroxide in aqueous glycols, to the corresponding thienyl-(3 )-alkanoic acids or their salts, converting them into their reactive functional derivatives, e.g. the halides thereof, for example, by reacting the acids with thionyl or phosphorus halides and condensing the resulting acid halides with the corresponding guanidines containing at least one hydrogen atom bound to nitrogen. Thienyl-3-carboxylic acids can be prepared from the above-mentioned primary 3-(ahydroxyalkyl)-thiophenes, i.e. 3-hydroxymethylthiophenes, by oxidation, for example, with the use of heavy metal oxides, acids or their salts, such as chromium trioxide, chromic or permanganic acid or potassium permanganate.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. lnjectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageous-fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75%, preferably about 1 to 50% of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereone. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 The mixture of 6.78 g of 3-thenylamine, 8.34 g of 2-methyl-2-thiopseudourea hemisulfate and 65 ml of water is heated to 100 for 6 hours while stirring, and stirring is continued for 5 hours at room temperature. After standing for 2 days at room temperature, the mixture is evaporated under reduced pressure, the residue triturated with ethanol and recrystallized from methanol-ethanol, to yield the 3-thenylguanidine hemisulfate of the formula melting at l97-198.

The starting material is prepared as follows: To the stirred and refluxing mixture of 50 g of 3- methylthiophene, 150 ml of benzene and l g of benzoyl peroxide, the mixture of 81.2 g of N-bromo succinimide and l g of benzoyl peroxide is added during 12 minutes and the mixture stirred for 4 minutes longer. It is cooled in an ice bath, the precipitate formed filtered off, the residue washed with benzene and the filtrate evaporated. The residue is distilled and the fraction boiling at 68-77/2.2 mm Hg collected, to yield the 3-thenyl bromide.

The solution of 5 g thereof in 5 ml of dimethylformamide is added dropwise to the mixture of 5.7 g of potassium phthalimide and 20 m] of dimethylformamide while stirring under nitrogen. After stirring overnight at room temperature, ml of chloroform are added and the mixture poured onto ml of water. The organic layer is separated and the aqueous phase extracted with chloroform. The combined organic solutions are washed with 80 ml of 2N aqueous sodium hydroxide and water, dried, filtered, evaporated under reduced pressure and the residue triturated with diethyl ether, to yield the N-(3-thenyl)-phthalimide, melting at -l32.

The mixture of 85.4 g thereof, 50 ml of hydrazine hydrate and 1.5 liter of methanol is refluxed for 3% hours while stirring, during which time it is diluted with another liter of methanol. It is cooled, acidified with concentrated hydrochloric acid to a pH=2 and again refluxed for 1% hours. After cooling, it is filtered, the residue washed with methanol and the filtrate evaporated under reduced pressure. The residue is taken up in water, the mixture filtered, the filtrate made basic with 6N aqueous sodium hydroxide and saturated with sodium carbonate. The mixture is extracted with diethyl ether, the extract dried, filtered, evaporated, the residue distilled and the fraction boiling at 6567/3 mm Hg collected, to yield the 3-thenylamine.

EXAMPLE 2 To 12 g of l-( 3-thenyl)-2,3-dimethyl-2- thiopseudourea, 10% sulfuric acid is added while cooling until a pH=4.5 is reached. Hereupon 60 m1 of 40% aqueous methylamine are added followed by 60 m1 of methanol and the mixture is refluxed for 20 hours under nitrogen. It is evaporated under reduced pressure, the residue triturated with isopropanol and recrystallized from methanol-isopropanol, to yield the l- (3-thenyl)-2,3-dimethylguanidine hemisulfate of the formula melting at 27l272 with decomposition; its hemihydrate melts at 262 (dec.).

The starting material is prepared as follows: To the solution of l 1.3 g of 3-thenylamine in 75 ml of diethyl ether, 7.3 g of methylisothiocyanate in 25 ml of diethyl ether are added during 5 minutes while stirring. After 2 hours, the supernatant solution is decanted off, the residue washed with diethyl ether and the washings again decanted off, to yield the l-(3-theny|)-3- methylthiourea, melting at 687l.

The mixture of l8.6 g thereof, 12.5 ml of methyl iodide and 100 ml of methanol is refluxed for 2 hours and evaporated under reduced pressure. The residue is recrystallized from isopropanol, to yield the l-(3-thenyl 2,3-dimethyl-2-thiopseudourea hydroiodide melting at l46-l47. It is taken up in water, 20 g of sodium carbonate are added and the mixture extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the corresponding free base.

EXAMPLE 3 The mixture of 6.78 g of 3-thenylamine, 9.9 g of Z-methyl-mercapto-imidazoline hemisulfate and 65 ml of water is heated to 100 for 6 hours while stirring and allowed to stand overnight at room temperature. It is evaporated under reduced pressure, the residue taken up in hot methanol, the solution filtered and the filtrate diluted with isopropanol. The precipitate formed after cooling in ice is filtered off, the residue triturated with ethanol and again recrystallized from methanolisopropanol, to yield the 2-(3-thenyl-amino)-2- imidazoline l-( 3-thenyl )-2,3-ethyleneguanidine] hemisulfate of the formula 439m; H l N=AJNH -1/2HQSO4 S (CH2):

melting at l83-l89.

EXAMPLE 4 (HI-N HCH:

melting at 280 with decomposition.

The starting material is prepared as follows: The mixture of 10 g of 2,5-dichlor0-3-thenyl chloride, 7 g of hexamethylene-tetramine and ml of chloroform is stirred for 4 hours at 45 and evaporated under reduced pressure, to yield the l-(2,5dichloro-3-thenyl)- hexamethylenetetrammonium chloride melting at 205-207 with decomposition.

The mixture of 10.6 g thereof, 40 ml concentrated hydrochloric acid and 50 ml of methanol is refluxed for 50 minutes, concentrated at normal pressure and evaporated under reduced pressure. The residue is taken up in water, the mixture made basic with 6N aqueous sodium hydroxide and saturated with sodium carbonate. It is extracted with diethyl ether, the extract dried, filtered, evaporated, the residue distilled and the fraction boiling at 9l/l.7 mm Hg collected, to yield the 2,5-dichloro-3-thenyl-amine.

The mixture of 10 g thereof, 4 g of methylisothiocyanate and 75 ml of diethyl ether is stirred for 1 /2 hours at room temperature and allowed to stand overnight. The precipitate formed on scratching is filtered off and washed with diethyl ether, to yield the l-( 2,5-dichloro- 3-thenyl)-3-methylthiourea, melting at 98-l00.

The mixture of l l g thereof, 5.4 ml of methyl iodide and 50 ml of methanol is refluxed for 2 hours and evaporated under reduced pressure. The residue is taken up in the minimum amount of hot isopropanol, the solution cooled to room temperature, filtered and the filtrate cooled in ice. The precipitate formed is washed with cold isopropanol and dried under reduced pressure, to yield the l-(2,5-dichloro-3-thenyl )-2,3- dimethyl-Z-thiopseudourea hydroiodide melting at ll8ll9. It is taken up in water, the solution saturated with sodium carbonate and extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the corresponding free base.

EXAMPLE 5 Preparation of 10,000 tablets each containing 50.0 mg of the active ingredient:

Formula:

l 3-thenyl )-2,3-dimethylguanidine hemisulfate 500.0 g Lactose l 706.0 g Corn starch 90.0 g Polyethylene glycol 6,000 90.0 g Talcum powder 90.0 g Magnesium stearate 24.0 g Purified water qs.

and compressed into tablets using concave punches with 7.1 mm diameter, uppers bisected.

EXAMPLE 6 To 6.7 g of l-[ l-(3-thienyl)-ethyl]-2,3-dimethyl-2- thiopseudourea. 1.6 g of sulfuric acid is added and the pH adjusted to 6.2 with a small amount of aqueous sodium hydroxide. Hereupon 30 ml of 40% aqueous methylamine are added, followed by 50 ml of methanol and the mixture is refluxed for 20 hours under nitrogen. It is evaporated under reduced pressure, the residue triturated with isopropanol and recrystallized from methanol-isopropanol, to yield the l-[ l-( 3-thienyl)- ethyll-2,3-dimethylguanidine hemisulfate of the formula melting at l96-200 with decomposition.

The'starting material is prepared as follows: To the mixture of 3.6 g of lithium wire and 100 ml of diethyl ether is added 34.4 g of butyl bromide at a rate to maintain the temperature at l. The reaction mixture is allowed to warm up to 0l0 for 2 hours. The unreacted lithium is filtered off and the filtrate cooled to 70, whereupon the solution of 32.6 g of 3- bromothiophene in 100 ml of diethyl ether is added. The mixture is stirred for minutes and the solution of 20 g of N,N-dimethylacetamide in 50 ml of diethyl ether is added. The resulting mixture is stirred at 70 for 1 hour, poured over ice, acidified with concentrated hydrochloric acid and the layers separated. The organic layer is dried and evaporated. The residue is distilled under reduced pressure to give the 3- acetylthiophene boiling at 77-90/2.8 mm Hg.

The mixture of 5.8 g thereof, 8.3 g of O-methylhydroxylamine hydrochloride, 25 ml of pyridine and 40 ml of ethanol is refluxed for 16 hours. On cooling, the mixture is extracted with chloroform; the chloroform solution is washed with dilute aqueous hydrochloric acid, water and dried. The chloroform solution is evaporated to an oil, being the O-methyl-3-acctylthiophene oxime.

To the mixture of 17.9 g thereof and 100 ml of tetrahydrofuran, 300 ml of a 1 molar solution of diborane in tetrahydrofuran are added at l0. The resulting mixture is allowed to warm to room temperature and then refluxed for 2 hours. On cooling, 50 ml of ethanol are added cautiously. followed by a solution of hydrogen chloride in ethyl acetate until the reacting mixture is acidic. The resulting mixture is evaporated under reduced pressure and the residue partitioned between diethyl ether and water. The aqueous layer is made basic with 6N aqueous sodium hydroxide and the basic solution extracted with diethyl ether. The ether extract is dried and evaporated to afford as an oil the 3-( l-aminoethyl)-thiophene. To the solution of 6.4 g thereof in 50 ml of diethyl ether, 3.7 g of methylisocyanate in 25 ml of diethyl ether are added during 5 minutes while stirring. After two hours, the supernatant solution is decanted, the residue washed with diethyl ether and the washings again decanted to yield the l- 10 l-( 3-thienyl )-ethyl]-3-methylthiourea, 88-90.

The mixture of 5.7 g thereof, 3.8 ml of methyl iodide and 50 ml of methanol is refluxed for 2 hours and evaporated under reduced pressure. The residue is recrystallized from isopropanol, to yield the l-[ l-( 3-thienyl ethyl1-2,3dimethyl-Z-thiopseudourea hydroiodide melting at l35l36. It is taken up in water, [0 g of sodium carbonate are added and the mixture extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the corresponding free base.

EXAMPLE 7 The mixture of 3 g of 3-(2-aminoethyl)-thiophene, 3.3 g of 2-methyl-2-thiopseudourea hemisulfate and 30 ml of water is heated to for 6 hours while stirring, and stirring is continued for 5 hours at room temperature. After standing overnight, the mixture is evaporated under reduced pressure, the residue triturated with isopropanol and recrystallized from methanolethanol, to afford the 2-(3-thienyl)-ethylguanidine hemisulfate of the formula melting at l42l45.

The starting material is prepared as follows: The solution of 17.7 g of 3-thenyl bromide in 10 ml of dimethylformamide is added over a 10 minute period to the mixture of 7.35 g of sodium cyanide and 50 ml of dimethylforrnamide. The reaction temperature rises to about 55 and the mixture is then cooled to about 40 where the temperature is maintained. After the addition, the mixture is heated to 70 for 1 hour. On cooling, it is poured into ml of water. The mixture is extracted with diethyl ether, the extract washed with water, dried, filtered and evaporated. The residual oil is distilled under reduced pressure to give the (3-thienyl)- acetonitrile boiling at 82-93/2 mm Hg.

To the mixture of 5.55 g thereof and 40 ml of tetrahydrofuran is added, dropwise, 60 ml of a 1 molar solution of diborane in tetrahydrofuran at about 20. The reacting mixture is allowed to stir at room temperature for 3 hours and is decomposed by the cautious addition of 15 ml of ethanol and then made acidic by the addition by the addition of a solution of hydrogen chloride in ethyl acetate. After stirring for 1 hour, the solids are collected on a filter, washed with ethyl acetate and dried, to yield the 3-(2-aminoethyl)-thiophene hydrochloride, melting at 2l0-2l2. It is taken up in water, l0 g of sodium carbonate are added and the mixture extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the corresponding free base.

melting at EXAMPLE 8 To 7.4 g of l-(3-thenyl)-2-methyl-3-ethyl-2- thiopseudourea is added l.7 g of concentrated sulfuric acid while cooling and the pH is then adjusted to 6.2 with aqueous sodium hydroxide. Hereupon 25 ml of 70% aqueous ethylamine are added, followed by 25 ml of ethanol and the mixture is refluxed for 12 hours in a nitrogen atmosphere. The reaction mixture is evaporated under reduced pressure, the residue triturated with isopropanol and recrystallized from ethanolmethanol, to yield the l(3-thenyl)-2,3- diethylguanidine hemisulfate of the formula melting at 2l22l3.

The starting material is prepared as follows: To the solution of 7 g of 3-thenylamine in 50 ml of diethyl ether, 4.8 g of ethylisothiocyanate in 25 ml of diethyl ether are added during 5 minutes while stirring. After 2 hours, the supernatant solution is decanted and the oily residue crystallized, to yield the l-(3-thienyl)-3- ethylthiourea, melting at 98l0l.

The mixture of 8.2 g thereof, 5 ml of methyl iodide and 50 ml of methanol is refluxed for 2 /2 hours and evaporated under reduced pressure. The residue is recrystallized from isopropanol, to yield the l-(3-thenyl)- 2-methyl-3-ethyl-2-thiopseudourea hydroiodide, melting at l06l 07. It is taken up in water, g of sodium carbonate are added and the mixture extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the corresponding free base.

EXAMPLE 9 the l-[2-(3-thienyl)-ethyll-2,3-dimethylguanidine hemisulfate of the formula tCH1CH,NHC--NHCHa H N-CH: .1/2H SO,

melting at l80-l 82 with decomposition.

The starting material is prepared as follows: To the solution of 7 g of 3-( Z-aminoethyU-thiophene in 50 ml of diethyl ether, 4.02 g of methylisothiocyanate in ml of diethyl ether are added during 5 minutes while stirring. After 4 hours, the solution is seeded, thereby obtaining the crystalline l-[2-(3-thienyl)-ethyl]3- methylthiourea.

The mixture of 9.6 g thereof, 6.3 ml of methyl iodide and 60 ml of methanol is refluxed for 2 hours and evaporated under reduced pressure. The residue is recrystallized from isopropanol, to yield the l-[2-(3-thienyl)- ethyl]-2,3-dimethyl-2-thiopseudourea hydroiodide. It is taken up in water, 10 g of sodium carbonate are added and the mixture extracted with diethyl ether. The extract is dried. filtered and evaporated, to yield the corresponding free base.

EXAMPLE l0 The mixture of 3.2 g of 2,5-dimethyl-3-thenylamine. 3.17 g of 2-methyl-2-thiopseudourea hemisulfate and ml of water is heated to 100 for 6 hours. After standing overnight at room temperature. isopropanol is added to precipitated product. It is recrystallized from methanol, to yield the 2,5-dimethyl-3-thenylguanidine hemisulfate of the formula melting at 200204.

The starting material is prepared as follows: To the solution of 22.4 g of 2,5-dimethylthiophene in 50 ml of glacial acetic acid, the solution of 20.2 g of chloromethyl methyl ether in 10 ml of glacial acetic acid are added over a 15 minute period at O-3. The resulting solution is stirred for k hour and then allowed to warm up to room temperature and stirred for an additional 3 hours. The reaction mixture is poured onto 300 ml water and extracted with 4 portions of diethyl ether. The combined extracts are washed with water, aqueous sodium bicarbonate, dried, filtered and evaporated. The residual oil is distilled under reduced pressure to afford the 2,5-dimethyl-3-chloromethylthiophene, boiling at 80-90/2 mm Hg.

The mixture of 14.9 g thereof, l7.6 g of potassium phthalimide and ml of dimethylformamide is stirred for 20 hours at room temperature. Thereupon 75 ml of chloroform are added and the resulting mixture poured into water. The layers are separated and the aqueous layer extracted with chloroform. The extract is washed with 1N aqueous sodium hydroxide and water, dried, filtered and evaporated. The residual solid is recrystallized from isopropanol, to yield the 2,5-dimethyl-3- phthalimidomethylthiophene, melting at l l l-l 12.

To the mixture of l9.5 g thereof, 1 1 ml of hydrazine hydrate and 500 ml of methanol is refluxed for 3 /2 hours, It is cooled, acidified with 20 ml of concentrated hydrochloric acid and again refluxed for 1 hours. After cooling, it is filtered, the residue washed with methanol and the filtrate evaporated under reduced pressure. The residue is taken up in water, the mixture filtered, the filtrate made basic with 6N aqueous sodium hydroxide and saturated with sodium carbonate. The mixture is extracted with diethyl ether, the extract dried, filtered, evaporated, the residue distilled and the fraction boiling at 6l-63/1.2 mm Hg collected, to yield the 2,S-dimethyl-S-thenylamine.

EXAMPLE 1 I To 12.2 g of l-(2,5-dimethyl-3-thenyl)-2,3-dimethyl- Z-thiopseudourea, 10% aqueous sulfuric acid is added until a pH of 4 is reached. Hereupon 75 ml of 40% aqueous methylamine are added, followed by 75 ml of methanol and the mixture is refluxed for 20 hours under nitrogen. it is evaporated under reduced pressure, the residue triturated with isopropanol and recrystallized from methanol-isopropanol, to yield the l- (2,5-dimethyl-3-thenyl)-2,3-dimethylguanidine hemisulfate of the formula melting at 290 with decomposition.

The starting materials are prepared as follows: To the solution of 10 g of 2,5-dimethyl-3-thenylamine in 75 ml of diethyl ether, 5.2 g of methylisothiocyanate and 25 ml of diethyl ether are added during 5 minutes while stirring. After 2 hours the solution is seeded, thereby obtaining the crystalline l-(2,5-dimethyl-3-thenyl)-3- methylthiourea, melting at 8 l-83.

The mixture of 13 g thereof, 7.6 ml of methyl iodide and 75 ml'of methanol is refluxed for 2 hours and evaporated under reduced pressure. The residue is recrystallized from isopropanol, to yield the l-(2,5-dimethyl- 3-thenyl)-2,3-dimethyl-2-thiopseudourea hydroiodide. It is taken up in water, 10 g of sodium carbonate are added and the mixture extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the corresponding free base.

EXAMPLE 12 The mixture of 9.7 g of 2-bromo-3-thenylamine, 7.9 g of trimethylisothiouronium chloride and 160 ml of isopropanol is refluxed for 16 hours. It is evaporated under reduced pressure, the residual oil taken up in 25 ml of water, made basic with 20 ml of 50% aqueous sodium hydroxide and extracted with toluene. The extract is evaporated under reduced pressure and the residue taken up in 100 ml of isopropanol. The resulting solution is neutralized by the addition of 2.59 g of 94.5% aqueous sulfuric acid. The solution is cooled, the solids formed are collected on a filter and washed with cold isopropanol. Recrystallization from isopropanol-water affords the l-(2-bromo-3-thenyl)-2,3- dimethylguanidine hemisulfate monohydrate of the formula melting at 277.

EXAMPLE 13 The mixture of 25 g of 2-chloro-3-thenylamine, 43.5 g of trimethylisothiouronium chloride and 250 ml of isopropanol is refluxed for 16 hours while stirring. It is evaporated under reduced pressure, the residue dissolved in 150 ml of water and the solution made basic with 25 ml of 50% aqueous sodium hydroxide while cooling with ice. The mixture is extracted with diethyl ether, the extract evaporated and the residue taken up in 200 ml of isopropanol. The solution is neutralized with 95% sulfuric acid, the mixture cooled to 0, filtered and the residue washed with isopropanol. It is recrystallized from aqueous isopropanol, to yield the l-(2-chloro-3-thenyl)-2,3-dimethylguanidine hemisulfate of the formula melting at 283 with decomposition.

The starting material is prepared as follows: To the solution of 20 g of 2-chloro-3-methylthiophene in 100 ml of carbon tetrachloride, the mixture of 30 g of N- bromosuccinimide, l g of benzoyl peroxide and 50 ml of carbon tetrachloride is added while stirring at 55. The mixture is refluxed until its color changes and the foaming subsides. It is quickly cooled to 20, filtered, the residue washed with carbon tetrachloride and the filtrate evaporated under reduced pressure, to yield the 2-chloro-3-thenylbromide.

To the solution of 42 g thereof in 175 ml of chloroform and 21 ml of dimethylforrnamide, g of potas sium phthalimide are added and the mixture stirred at 55 for 2 days. It is cooled to 20, diluted with 200 ml of chloroform and 200 ml of water, the aqueous layer separated and extracted with 150 ml of warm chloroform. The combined extract is washed with water, dried and evaporated under reduced pressure. The residue is dissolved in 80 ml of isopropanol and the solution allowed to stand overnight in the refrigerator. The precipitate formed is filtered off, washed with isopropanol and recrystallized from isopropanol with the aid of charcoal, to yield the N-(2-chloro-3-thenyl)- phthalimide.

The mixture of 22 g thereof, 1 1.1 ml of hydrazine hydrate and 120 ml of water is refluxed for 5 hours. After cooling 20 ml of concentrated hydrochloric acid are added and the mixture refluxed for 3 hours. It is cooled, filtered and the pH of the filtrate adjusted to 12 with 50% aqueous sodium hydroxide. it is extracted with diethyl ether, the extract dried, evaporated, the residue distilled and the fraction boiling at /7 mm Hg collected, to yield the 2-chloro-3-thenylamine.

We claim:

1. A pharmaceutical composition comprising a hypotensively effective amount of a compound of the forwherein each of R and R is hydrogen, lower alkyl or halogeno, each of R and R is hydrogen or lower alkyl, R and R separately are hydrogen or lower alkyl or, when taken together, lower alkylene of up to 4 carbon atoms separating the adjacent nitrogen atoms by at least 2 carbon atoms and C,, H is a straight or branched alkylene chain of up to 4 carbon atoms, or a therapeutically useful acid addition salt thereof, and a pharmaceutical excipient.

2. A composition as claimed in claim 1, wherein the effective compound is that of the formula wherein each of R and R is hydrogen, methyl, chloro or bromo, each of R R and R is hydrogen or methyl or R and R together represent 1,2-ethylene or a therapeutically useful acid addition salt thereof.

3. A composition as claimed in claim 1, wherein the effective compound is the 1-(3-thenyl)-2,3- dimethylguanidine or a therapeutically useful acid addition salt thereof.

4. A composition as claimed in claim 1, wherein the effective compound is the l-( 3-thenyl)-2,3-

dimehtylguanidine hemisulfate. 

2. A composition as claimed in claim 1, wherein the effective compound is that of the formula
 3. A composition as claimed in claim 1, wherein the effective compound is the 1-(3-thenyl)-2,3-dimethylguanidine or a therapeutically useful acid addition salt thereof.
 4. A composition as claimed in claim 1, wherein the effective compound is the 1-(3-thenyl)-2,3-dimehtylguanidine hemisulfate. 